Fusobacterium nucleatum in Colorectal Carcinoma Tissue According to Tumor Location - PubMed (original) (raw)

doi: 10.1038/ctg.2016.53.

Yin Cao 2 3 4, Andrew T Chan 2 3 5, Zhi Rong Qian 1, Jonathan A Nowak 6, Yohei Masugi 1, Yan Shi 1, Mingyang Song 2 3 4, Annacarolina da Silva 1, Mancang Gu 1, Wanwan Li 1, Tsuyoshi Hamada 1, Keisuke Kosumi 1, Akiko Hanyuda 1, Li Liu 1, Aleksandar D Kostic 7 8 9, Marios Giannakis 1 8 10, Susan Bullman 1 8, Caitlin A Brennan 11, Danny A Milner 6 11, Hideo Baba 12, Levi A Garraway 1 8 10, Jeffrey A Meyerhardt 1, Wendy S Garrett 1 8 11, Curtis Huttenhower 7 8 13, Matthew Meyerson 1 8, Edward L Giovannucci 4 5 14, Charles S Fuchs 1 5, Reiko Nishihara 1 4 7 14, Shuji Ogino 1 6 14

Affiliations

Fusobacterium nucleatum in Colorectal Carcinoma Tissue According to Tumor Location

Kosuke Mima et al. Clin Transl Gastroenterol. 2016.

Abstract

Objectives: Evidence suggests a possible role of Fusobacterium nucleatum in colorectal carcinogenesis, especially in right-sided proximal colorectum. Considering a change in bowel contents and microbiome from proximal to distal colorectal segments, we hypothesized that the proportion of colorectal carcinoma enriched with F. nucleatum might gradually increase along the bowel subsites from rectum to cecum.

Methods: A retrospective, cross-sectional analysis was conducted on 1,102 colon and rectal carcinomas in molecular pathological epidemiology databases of the Nurses' Health Study and the Health Professionals Follow-up Study. We measured the amount of F. nucleatum DNA in colorectal tumor tissue using a quantitative PCR assay and equally dichotomized F. nucleatum-positive cases (high vs. low). We used multivariable logistic regression analysis to examine the relationship of a bowel subsite variable (rectum, rectosigmoid junction, sigmoid colon, descending colon, splenic flexure, transverse colon, hepatic flexure, ascending colon, and cecum) with the amount of F. nucleatum.

Results: The proportion of F. nucleatum-high colorectal cancers gradually increased from rectal cancers (2.5%; 4/157) to cecal cancers (11%; 19/178), with a statistically significant linear trend along all subsites (P<0.0001) and little evidence of non-linearity. The proportion of F. nucleatum-low cancers was higher in rectal, ascending colon, and cecal cancers than in cancers of middle segments.

Conclusions: The proportion of F. nucleatum-high colorectal cancers gradually increases from rectum to cecum. Our data support the colorectal continuum model that reflects pathogenic influences of the gut microbiota on neoplastic and immune cells and challenges the prevailing two-colon (proximal vs. distal) dichotomy paradigm.

PubMed Disclaimer

Conflict of interest statement

Guarantor of the article: Shuji Ogino, MD, PhD, MS.

Specific author contributions: All authors contributed to review and revision. Kosuke Mima, Caitlin A. Brennan, Danny A. Milner, Levi A. Garraway, Jeffrey A. Meyerhardt, Wendy S. Garrett, Curtis Huttenhower, Matthew Meyerson, Edward L. Giovannucci, Andrew T. Chan, Charles S. Fuchs, and Shuji Ogino developed the main concept and designed the study. Andrew T. Chan, Charles S. Fuchs, and Shuji Ogino wrote grant applications. Kosuke Mima, Yin Cao, Reiko Nishihara, Zhi Rong Qian, Jonathan A. Nowak, Yohei Masugi, Yan Shi, Annacarolina da Silva, Mancang Gu, Wanwan Li, Tsuyoshi Hamada, Keisuke Kosumi, Akiko Hanyuda, Li Liu, Mingyang Song, Jeffrey A. Meyerhardt, Edward L. Giovannucci, Andrew T. Chan, Charles S. Fuchs, and Shuji Ogino were responsible for collection of tumor tissue and acquisition of epidemiological, clinical and tumor tissue data, including histopathological and immunohistochemical characteristics. Kosuke Mima, Aleksandar D. Kostic, Susan Bullman, Caitlin A. Brennan, Wendy S. Garrett, Curtis Huttenhower, Matthew Meyerson, Charles S. Fuchs, and Shuji Ogino performed data analysis and interpretation. Kosuke Mima, Yin Cao, Reiko Nishihara, and Shuji Ogino drafted the manuscript. Yin Cao, Andrew T. Chan, Mingyang Song, Marios Giannakis, Caitlin A. Brennan, Hideo Baba, Wendy S. Garrett, Matthew Meyerson, Jeffrey A. Meyerhardt, Edward L. Giovannucci, Charles S. Fuchs, Reiko Nishihara, and Shuji Ogino contributed to editing and critical revision for important intellectual contents. All authors approved the final draft submitted.

Financial support: This work was supported by US National Institutes of Health (NIH) grants (P01 CA87969 to M.J. Stampfer; UM1 CA186107 to M.J. Stampfer; P01 CA55075 to W.C. Willett; UM1 CA167552 to W.C. Willett; P50 CA127003 to C.S.F.; R01 CA137178 to A.T.C.; R01 CA151993 to S.O.; R35 CA197735 to S.O.; and K07 CA190673 to R.N.); and by grants from the Project P Fund, The Friends of the Dana-Farber Cancer Institute, Bennett Family Fund, and the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance. K.M. is supported by a grant from Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers from Japan Society for the Promotion of Science. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Potential competing interests: Chan previously served as a consultant for Bayer Healthcare, Millennium Pharmaceuticals, Pozen, and Pfizer. This study was not funded by Bayer Healthcare, Millennium Pharmaceuticals, Pozen, or Pfizer. This is redundant, and we will keep the last sentence. Meyerson has applied for a patent on Fusobacterium in colorectal cancer diagnosis and had ownership interest in and was a consultant and advisory board member for Foundation Medicine. He also receives research support from Bayer. The other authors declare no competing financial interest.

Figures

Figure 1

Figure 1

Proportions of _Fusobacterium nucleatum_-negative, _F. nucleatum_-low, and _F. nucleatum_-high colorectal carcinoma cases along the bowel subsites. _P_-value was calculated by the linear trend test across the bowel subsite variable (population average distance from anal verge to each subsite (cm)) as a continuous variable in the univariable logistic regression model to predict the amount of tissue F. nucleatum (as a binary outcome variable (high vs. low/negative)).

Similar articles

Cited by

References

    1. Louis P, Hold GL, Flint HJ. The gut microbiota, bacterial metabolites and colorectal cancer. Nat Rev Microbiol 2014; 12: 661–672. - PubMed
    1. Keku TO, Dulal S, Deveaux A et al. The gastrointestinal microbiota and colorectal cancer. Am J Physiol Gastrointest Liver Physiol 2015; 308: G351–G363. - PMC - PubMed
    1. Ericsson AC, Akter S, Hanson MM et al. Differential susceptibility to colorectal cancer due to naturally occurring gut microbiota. Oncotarget 2015; 6: 33689–33704. - PMC - PubMed
    1. Dejea CM, Wick EC, Hechenbleikner EM et al. Microbiota organization is a distinct feature of proximal colorectal cancers. Proc Natl Acad Sci USA 2014; 111: 18321–18326. - PMC - PubMed
    1. Belcheva A, Irrazabal T, Robertson SJ et al. Gut microbial metabolism drives transformation of MSH2-deficient colon epithelial cells. Cell 2014; 158: 288–299. - PubMed

Grants and funding

LinkOut - more resources